Treatment of very young patients is particularly challenging due to concern over late effects of radiation therapy, and therefore radiation is typically deferred in children less than 3 years of age.

The Head Start trials are a group of studies that explore the use of high dose chemotherapy with autologous hematopoietic cell rescue (AuHCR) as a substitute for craniospinal radiation (CSI) in children under the age of 6 years.

Head Start I accrued patients from 1991-1997 and Head Start II from 1997-2003. After initial surgery, patients received five cycles of induction chemotherapy consisting of vincristine, cisplatin, cyclophosphamide and etoposide. Head Start II included methotrexate with each cycle. Following induction, all patients underwent myeloablative chemotherapy using carboplatin, thiotepa and etoposide with AuHCR. Irradiation was used only at relapse. This treatment paradigm eliminated the need for CSI in about 50% of young children with non-metastatic medulloblastoma however, the mortality due to acute toxicity was 20%.

Head Start III was developed with the goal of determining whether high dose chemotherapy with AuHCR delivered over a short period of time (< 6 months) without radiation therapy is a feasible approach in the management of children less than 6 years of age with medulloblastoma who had a complete response to initial treatment.

Children < 6 yrs, initially M1, but with localized or disseminated disease after chemotherapy à CSI to 2340 cGy.

All children > 6 yrs à CSI to 2340 cGy.

The primary objective was to determine 2 yr event-free survival (EFS) and overall survival (OS) for children with standard risk disease under 6 years of age, and high-risk disease under 10 years of age.

Standard risk was defined as non-disseminated (M0) disease with gross total resection (R0)

High risk disease was defined either by disseminated disease (M1) or incomplete resection (R1)

Results

2-yr EFS (%)

2-yr OS (%)

All patients

47

65

M0 (n=39)

63

80

M1 (n=51)

33

54

3-yr EFS (%)

3-yr OS (%)

Histology

All desmoplastic

89

86

All classical

26

58

All anaplastic

36

31

M0

M0 desmoplastic

93

93

M0 classical

41

71

M0 anaplastic

50

67

M1

M1 desmoplastic

82

90

M1 classical

21

55

M1 anaplastic

29

29

2 toxic deaths were observed due to high dose chemotherapy

13 patients received radiation per protocol guidelines, and no protocol violations occurred

3-year radiation-free EFS was 49% for all patients

In multivariate Cox regression analyses, histology was the only significant independent predictor of EFS after adjusting for metastatic status, initial extent of resection of the primary tumor, regimen, age and gender. Patients with desmoplastic histology had significantly better EFS than patients with classic tumors (HR = 0.11, 95% CI = 0.033, 0.35). Outcomes for patients with anaplastic and classical tumors were not significantly different from one another.

Authors’ Conclusions

52% of young patients under 6 years of age avoided CSI when treated with the Head Start III regimen.

The outcomes presented are the best survival data published on young children with medulloblastoma not receiving radiation therapy.

Implications

This study establishes the feasibility of eliminating radiation therapy in a cohort of patients under 6 years of age with standard risk medulloblastoma and complete response to initial therapy.

Event-free survival and overall survival data suggests that this technique is feasible and safe.

Avoidance of CSI may reduce late effects such as decreased height, neurocognitive deficits, and late solid organ dysfunction; however, these potential risks must be balanced against cancer-related outcomes. Outcomes for M0 patients with classical and anaplastic histologies in this study appear to be poorer than would be expected for M0 patients treated with CSI.

The number of high-dose chemotherapy treatment-related toxicities was far lower than seen in Head Start I and II.

The data presented represents the best survival data published to date for children with medulloblastoma for whom radiation is deferred. This is particularly impressive considering that 60% of the patients in this cohort had disseminated disease at presentation. This is in contrast to other similar studies where approximately 30% of patients had M1 disease at presentation.

Although these results are promising, prospective randomized controlled trials are needed to validate the results of Head Start I, II, and III. Direct comparison of survival and other outcomes for children treated with up front CSI versus deferred or delayed RT would be of great interest.

The potential of limited field radiotherapy to the posterior fossa only may also be of interest for very young children with medulloblastoma. This type of treatment has potential to decrease local failures while avoiding many of the sequelae associated with CSI.